1. Field of the Invention
This invention relates to echogenic coatings for biomedical devices, and methods of preparing them. The coatings include echogenic irregularities and dramatically improve the visibility of the devices when viewed using ultrasound imaging techniques.
2. Background Information
Ultrasonic imaging has many applications. This technology is especially valuable for medical imaging applications because diagnostic ultrasound procedures are safe, very acceptable to patients and less expensive than other digital imaging technologies such as CT or MRI. Also, instruments are widely available and images are produced in real time. However, currently the contrast resolution of ultrasound is not as good as the other technologies. Hence, improvements in image quality open the door to rapid growth of this technique.
A variety of ultrasound contrast agents are known. These include porous uniformly-sized non-aggregated particles as described in Violante and Parker, Ser. No. 08/384,193. Such contrast agents may enhance the visibility of target tissue into which they are injected, but they can not enhance the ultrasound visibility of insertable medical devices.
In many medical procedures, the ability to accurately place a device within a tissue or passageway, especially within a suspected lesion, such as an abscess, cyst, tumor, or in a specific organ such as kidney or liver, is very important to complete the diagnosis or therapy of a patient. Such devices include needles, catheters, stents, dilators, introducers, angiography and angioplasty devices, pacemakers, in-patient appliances such as pumps, and artificial joints. Fine needle biopsy, fluid drainage, catheter placement for angiography, angioplasty, amniocentesis, or drug delivery are a few examples of medical procedures requiring accurate placement of medical devices. Inaccurate device placement may create a need to repeat a procedure thereby adding to medical care costs and patient discomfort or may, in some cases, result in a false negative diagnosis for example if a biopsy needle missed a lesion. Worse, misplacement may harm a patient directly.
Most medical devices, including catheters, have an acoustic impedance similar to that of the tissue into which the device is inserted. Consequently visibility of the device is poor and accurate placement becomes extremely difficult if not impossible. Another problem affecting the visibility of devices is the scattering angle. For example, stainless steel needles have an acoustic impedance significantly different from tissue and are highly visible under ultrasound imaging when the needle is in the plane of the ultrasound beam, but if the needle is moved to some other angle off-axis, the ultrasound beam is scattered in a direction other than the transducer and the needle becomes less visible or even invisible under ultrasound imaging.
Both of the problems described above have been addressed by efforts to increase the scattering power of the device so that the device becomes visible even when it is not completely in the plane of the ultrasound beam. U.S. Pat. No. 4,401,124 describes enhancing the scattering power of a needle by means of grooves in the tip of the device. This approach improves the angle of echo scattering, but the intensity of the scattered signal is less than ideal, and at any angle other than the optimum, signals are lost into the background speckle.
Another approach to improve the echogenicity of devices is set forth in Bosley et al., U.S. Pat. No. 5,201,314. This patent describes a material having an acoustic impedance different from that of the surrounding medium, and improved scattering. The material may be the device itself or a thin interface layer including hard particles such as metal or glass. The presence of spherical indentations formed or embossed on the device surface is said to produce enhanced scattering.
One problem with this approach is that the interface layer is generated during the extrusion process for forming a plastic device, or by soldering, or ion beam deposition, which are inapplicable to many devices, and are expensive and difficult to control. Also the differences in acoustical properties between glass or metal and body cavities are not very large, so echogenicity is not greatly enhanced. Further, the described devices are not smooth since the echogenicity is produced either by indentations in the surface or the addition of metal or glass balls of diameter greater than the thickness of the interface layer. The presence of the particles complicates the manufacturing process, and may weaken the surface of the device which can lead to sloughing of particles, device failure, or instability of the desired effect. Such coatings have not found their way into the market.
This invention satisfies a long felt need for improving the ultrasound imaging of biomedical devices. The coatings of the invention provide highly echogenic devices which are readily recognized from surrounding tissue or fluid under ultrasound imaging.
The invention succeeds at providing a broadly applicable method of enhancing the ultrasound visibility of surfaces, an objective which previous efforts have failed to reach. The invention solves two problems of the prior artxe2x80x94providing the medical device with an acoustic impedance quite different from that of the animal or human tissue into which it is placed (high acoustic impedance differential), and increasing ultrasound scatteringxe2x80x94by a simple, inexpensive, reproducible means of applying a polymer composite coating that has acoustical irregularities. The coatings of the invention are easily made by a variety of methods. They do not require solid particles or particle preparations and do not require machining or extrusion, elements employed in the prior art. Nonetheless, the coatings of the invention provide improved echogenicity.
An adherent, smooth coating employing acoustical irregularities to provide an increased acoustical impedance differential and increased ultrasound scattering differs from prior approaches, and was not previously known or suggested. Such a coating provides advantages that were not previously appreciated, such as broad applicability, the possibility of applying the coating after the device is manufactured, low cost, uniformity, and adaptability to be combined with other coating technologies such as lubricious coatings and coatings containing pharmaceutical agents.
A coated device prepared according to this invention is easily discernable under ultrasound imaging regardless of the angle to the transducer. Since the device is easily recognized against the background tissue or fluid, its exact location is easily identified. This positional certainty can greatly facilitate medical procedures such as biopsies, abscess drainage, chemotherapy placement, etc.
The coatings of the invention include echogenic features, such as discrete gas bubbles and pores, providing acoustically reflective interfaces between phases within or on the coated surface. These interfaces provide an acoustical impedance differential that is large, preferably several orders of magnitude. The shape of the bubbles or other gaseous spaces also improves scattering so that a device may be imaged at virtually any angle.
The advantages and objectives of the invention may be achieved by entrapping gas bubbles in a smooth, thin, biocompatible coating which can be applied to virtually any biomedical device. Gas bubbles are desirable to provide an acoustic impedance mismatch (acoustical impedance differential) much greater than can be obtained by previous inventions. Gas bubbles, especially of small diameter less than about 10 microns, are difficult to stabilize, and satisfactory methods for producing them are a further advantage of this invention. The presence of bubbles entrapped in a thin coating, preferably about 5 to about 50 microns thick, greatly enhances the echogenicity of the device while leaving the device surface very smooth so as to be virtually undetectable by the patient or physician.
According to the invention, a general method for increasing the echogenicity of an object when placed in an ambient material and subjected to ultrasound comprises: providing a coating liquid comprising a film-forming constituent; applying the coating liquid to the object; allowing the film-forming constituent to form a film comprising a solid matrix; and providing the film with an echogenic structure presenting echogenicity-increasing gas/non-gas interfaces when the object is placed in the ambient material. The echogenic features are preferably discrete compressible gaseous spaces enclosed within the film, pores capable of entrapping gas when the object is placed in the ambient material, or combinations.
The method preferably comprises including a reactive material in the coating liquid, and contacting the reactive material with a reactor to produce gas. In a preferred embodiment, the reactive material is a diisocyanate such as toluene diisocyanate or a diisocyanate prepolymer, the reactor is a hydrogen donor selected from the group consisting of liquid water, steam, water vapor, an alcohol, and an amine, and the gas is carbon dioxide. In other embodiments, the reactive material is a carbonate or bicarbonate salt, the reactor is an acid, and the gas is carbon dioxide; the reactive material is a diazo compound, the reactor is ultraviolet light, and the gas is nitrogen; the reactive material is a peroxide compound, the reactor is selected from the group consisting of an acid, a metal, thermal energy, and light, and the gas is oxygen.
The gas may be chlorine, hydrogen chloride or other gas with a vapor pressure higher than air.
In a preferred embodiment, the film-forming constituent is a reactive polymer-forming material, the applying step comprises reacting the reactive polymer-forming material to produce a polymer matrix and gas, and the echogenic features comprise features selected from the group consisting of discrete compressible gaseous spaces enclosed within the film, pores capable of entrapping gas when the object is placed in the ambient material, and combinations.
The method may comprise etching the film by chemical or physical means to produce the echogenic features.
The coating liquid may comprise a compound selected from the group consisting of perfluorocarbons, hydrocarbons, halogenated hydrocarbons, and other materials having a sufficiently high vapor pressure as to generate gas bubbles upon heating of the coating liquid to a predetermined temperature, and further comprising heating the coating liquid or the film to the predetermined temperature to produce gas bubbles.
The gaseous space may be produced by including in the coating a solid compound having a sublimation pressure sufficient to generate bubbles upon heating to a predetermined temperature, and heating the coating liquid or the film to the predetermined temperature to produce gas bubbles.
The coating liquid may be sonicated or otherwise agitated to produce bubbles from about 0.1 to about 300 microns, preferably from about 1 to about 50 microns, most preferably from about 5 to about 10 microns, before applying the coating liquid to the object. Alternatively, one may incorporate pre-formed polymer bubbles of a few microns in diameter within the coating liquid and hence in the polymer matrix. Another option is to include small particles with a diameter of a few microns with micropores on the order of 0.1 micron.
The film-forming component is preferably a dissolved polymer which is cast on a surface and from which the solvent is evaporated; a reactive monomer or pre-polymer reacted to form a polymer; or a thermosetting melted polymer solidifying upon cooling. The coating may involve reacting the polymerizing monomer or pre-polymer to produce a polymer matrix and gas, and trapping the gas in the polymer matrix, and/or allowing it to form micropores on the surface capable of entrapping gas when inserted into the target material. Isocyanate reacted with water to produce polyurethane and carbon dioxide is one example.
Another embodiment involves selecting the coating liquid such that the concentration of solvent is sufficiently high to dissolve the polymer, and the concentration of non-solvent is below the level at which the polymer will precipitate; and after applying the coating liquid, increasing the proportion of non-solvent to cause precipitation of a polymer matrix containing echogenic interfaces. The step of increasing the proportion of non-solvent may be evaporating the solvent, adding a non-solvent, or adding steam.
Before applying the echogenic polymer layer, a pre-coat and/or a base coat may be applied to the object. After the echogenic layer is applied, a top coat layer may be applied to the object without eliminating the increased echogenicity of the coating. If the echogenic layer has cavities, the top coat may reduce the wetability of the echogenic layer so as to promote the entrapment of air in the cavities.
Another aspect of the invention is a coating liquid for producing an echogenic coating on a substrate, comprising a liquid vehicle, a constituent that forms a coating when the coating liquid is applied to the substrate, and a means for providing gas/non-gas interfaces in the coating. The interface-providing means are preferably selected from the group consisting of gas bubbles in the coating liquid, a reactive material that generates gas upon reaction with a reactor, and a combination of components that causes precipitation of solids with entrapped gas during coating. The film-forming component is preferably selected from the group consisting of albumin, carboxylic polymers, cellulose, cellulose derivatives, gelatin, polyacetates, polyacrylics, ployacrylamides, polyamides, polybutyrals, polycarbonates, polyethylenes, polysilanes, polyureas, polyurethanes, polyethers, polyesters, polyoxides, polystyrenes, polysulfides, polysulfones, polysulfonides, polyvinylhalides, pyrrolidones, rubbers, and thermal-setting polymers.
The combination of components that causes precipitation of solids preferably comprises a solvent/non-solvent mixture and an inclusion-former, the concentration of solvent is sufficiently high to dissolve the inclusion-former in the coating liquid, and the concentration of non-solvent is sufficiently high to cause the inclusion-former to precipitate as an inclusion in the coating during evaporation of the solvent from the coating liquid, and to entrap gas.
In a third aspect of the invention, an object comprises a substrate and an echogenic surface or coating comprising a solid matrix and an echogenic structure that presents gas/non-gas interfaces at or near the surface of the object when the object is placed in an ambient medium, the interfaces providing the object with enhanced ultrasound visibility. The gas/non-gas interfaces preferably provide an acoustic impedance mismatch at the surface of the device of at least a factor of about 25.
The interfaces are preferably selected from the group consisting of interfaces between the matrix and discrete compressible gaseous spaces enclosed within the matrix, interfaces between the matrix and gas trapped in pores on the matrix, interfaces between gas trapped in pores on the matrix and the ambient medium, and combinations. The matrix preferably comprises a precipitate formed in the matrix and presenting echogenic gas/matrix interfaces. The echogenic structure preferably comprises gaseous spaces selected from the group consisting of pores, bubbles, channels, and cavities having a dimension selected from diameters or widths between 0.1 micron and about 300 microns, preferably between 1 micron and about 50 microns. More preferably the gaseous spaces are pores with a diameter of about 1 to about 10 microns, channels about 5 to about 50 microns wide and about 20 to about 500 microns long. The echogenic surface preferably consists essentially of the matrix and the gaseous spaces, or may further comprise solid precipitated material.
Preferably less than about 50%, more preferably about 10% to about 20% of the surface area of the object is made up of gaseous spaces. So long as the space holds gas, it appears that the size distribution of the gaseous spaces does not significantly affect the echogenicity of the coating. That is, a surface of many submicron spaces and a surface of a few multimicron sized spaces may be equally echogenic. The key features contributing to echogenicity are the total percentage of surface area made up by gaseous spaces, the compressibility of the spaces if they are enclosed (determined by the polymer, thickness, and diameter of the space), and the ability to entrap air when inserted into an ambient material if the spaces are open (determined by the diameter, shape, and hygroscopic nature of the space).
The gaseous spaces may be located within the echogenic layer or between the echogenic layer and a top layer or the target material. Preferably, the gaseous spaces must be compressible. If they are pores or channels with trapped gas exposed directly to the target material, they are suitably compressible. If the gaseous spaces are enclosed within the polymer matrix or covered by a top coat, the material separating the gaseous space from the target material must be thin enough and flexible enough that the gas remains compressible. A gaseous space separated from the material to be visualized by a hard or thick film is not likely to contribute much echogenicity. Preferably, the flexibility of any covering over the gaseous space is such that it does not significantly reduce the compressibility of the underlaying gas, for example by no more than one order of magnitude. This effect is best achieved if there is no more than several microns of coating material over the gaseous space, such as less than about 5 microns, preferably between about 1 and about 2 microns.
In summary, the echogenic structures included within the polymer matrix according to the invention may be open pores or channels capable of trapping air at the surface of the coating, closed bubbles or channels within the polymer matrix, pores or channels that are thinly covered with a top coat layer, and gas-entrapping intrinsically formed solid or semi-solid inclusions precipitated within the polymer matrix.
The gas/non-gas interfaces are preferably located within the matrix, between the matrix and a top layer, or between the matrix and the ambient material.
The substrate is preferably a medical device such as a catheter, needle, stent, hydrocephalus shunt, draintube, pacemaker, dialysis device, small or temporary joint replacement, urinary sphincter, urinary dilator, long term urinary device, tissue bonding urinary device, penile prosthesis, vascular catheter port, peripherally insertable central venous catheter, long term tunneled central venous catheter, peripheral venous catheter, short term central venous catheter, arterial catheter, PCTA or PTA catheter, and pulmonary artery Swan-Ganz catheter. The coating may further comprise a contrast agent for non-ultrasound imaging such as for x-ray or magnetic resonance imaging.
Further objectives and advantages will become apparent from a consideration of the description and drawings.